A multistep approach for exploring quality markers of Shengjiang Xiexin decoction by integrating plasma pharmacochemistry-pharmacokinetics-pharmacology.

Shengjiang Xiexin decoction (SXD), a well-known traditional Chinese medicine (TCM), was used to alleviate delayed-onset diarrhea induced by the chemotherapeutic agent irinotecan (CPT-11). Our previous study showed that SXD regulated multidrug resistance-associated protein 2 (Mrp-2) to alter the pharmacokinetics of CPT-11 and its metabolites. However, the pharmacodynamic constituents and the related quality markers of SXD are unclear. In this study, ultra-high performance liquid chromatography coupled with quadrupole orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) was utilized to identify the prototypes and metabolites in rat plasma after oral administration of SXD. The pharmacokinetic markers (PK markers) were screened through quantification and semiquantification of SXD-related xenobiotics in plasma using liquid chromatography-mass spectrometry (LC-MS) combined with statistical analysis. Computational molecular docking was performed to assess the potential binding ability of the PK markers with the target Mrp-2. The results were verified by evaluating the impact on Mrp-2 function using Caco-2 cells. The quality markers were chosen from these PK markers based on the binding affinities with Mrp-2, the specificity and the traceability. As a result, a total of 142 SXD-related exogenous components, including 77 prototypes and 65 metabolites, were detected in rat plasma. Among these, 83 xenobiotics were selected as PK markers due to their satisfactory pharmacokinetic behaviors. Based on the characteristics of quality markers, the prototype-based PK markers were considered the indices of quality control for SXD, including baicalin, baicalein, wogonoside, wogonin, liquiritigenin, isoliquiritigenin, norwogonin, oroxylin A, dihydrobaicalin, chrysin, glycyrrhizic acid, glycyrrhetinic acid, oroxylin A 7-O-glucuronide, liquiritin and isoliquiritin. This study provided an interesting strategy for screening the quality markers involved in the pharmacokinetics of SXD and its action target, which offered important information for the modernization of SXD and other TCM formulae.

Thioaptamer-conjugated CD44-targeted delivery system for the treatment of breast cancer in vitro and in vivo.

The high transfection efficiency and enhanced therapeutic effect of drug delivery systems developed in recent years imply that ligand-decorated nanocarriers are potentially targeted vectors for breast cancer treatment. Thioaptamer (TA)-modified nanoparticles (NPs) designed in this study mainly consisted of ligand TA and dendritic polyamidoamine (PAMAM). Knowing that TA can bind to CD44-receptors in breast cancer, this study was intended to validate the safety and feasibility of systemic miRNA delivery to breast cancer cells by TA-PEG-PAMAM/miRNA (polyethylene glycol - PEG), testify its tumor targeting efficiency in vitro, and observe its biodistribution when it was administered systemically to a xenograft mouse model of breast cancer. The in vivo and ex vivo imaging results in human breast cancer tumor-bearing mice showed that TA-modification was able to enhance the accumulation of NPs in the breast cancer tumor. Our data showed that TA-NPs did not induce functional impairment to normal tissues and vital organs. TA-NPs may prove to be a safe and effective miRNA deliver system for breast cancer treatment, and could be widely used in pre-clinical and eventually clinical arenas of breast cancer treatment.